Prescription patterns in people who are frail
Authors: Isca Hershkowitz, Avivit Cahn
Journal: The Lancet Healthy Longevity (2023)

In this issue of The Lancet Healthy Longevity, Malik and colleagues1Malik ME Butt JH Strange JE et al.Initiation of SGLT2 inhibitors and GLP-1 receptor agonists according to level of frailty in people with type 2 diabetes and cardiovascular disease in Denmark: a cross-sectional, nationwide study.Lancet Healthy Longev. 2023; (published online Sept 18.)https://doi.org/10.1016/S2666-7568(23)00164-2Google Scholar describe prescription patterns of SGLT2 inhibitors and GLP-1 receptor agonists according to frailty among people in Denmark with type 2 diabetes and cardiovascular disease. This cross-sectional, nationwide study is the first to assess the use of these agents according to frailty in a real-world setting. The American Diabetes Association promotes the use of SGLT2 inhibitors or GLP-1 receptor agonists as part of a glucose-lowering regimen in people with type 2 diabetes and a high risk of or already established cardiovascular disease.2ElSayed NA Aleppo G Aroda VR et al.Pharmacologic approaches to glycemic treatment: standards of care in diabetes—2023.Diabetes Care. 2023; 46: S140-S157Crossref PubMed Scopus (0) Google Scholar Nonetheless, real-world evidence shows that these guidelines are only partly implemented. In the 2019 CAPTURE study,3Mosenzon O Alguwaihes A Leon JLA et al.CAPTURE: a multinational, cross-sectional study of cardiovascular disease prevalence in adults with type 2 diabetes across 13 countries.Cardiovasc Diabetol. 2021; 20: 154Crossref PubMed Scopus (88) Google Scholar which was conducted in 13 countries, only 21·5% of people with established cardiovascular disease received either of these agents. New prescriptions for SGLT2 inhibitors and GLP-1 receptor agonists are increasing in Denmark, with prescriptions for SGLT2 inhibitors being double the number of prescriptions for GLP-1 receptor agonists, which is consistent with previous prescription trends in Denmark in 2014–17.4Knudsen JS Baggesen LM Lajer M et al.Changes in SGLT2i and GLP-1RA real-world initiator profiles following cardiovascular outcome trials: a Danish nationwide population-based study.PLoS One. 2020; 15e0229621Crossref Scopus (23) Google Scholar This incongruence has been attributed to the publication of cardiovascular-outcome trials of SGLT2 inhibitors since 2015 and the simpler administration route of SGLT2 inhibitors than of GLP-1 receptor agonists (ie, oral vs injectable).4Knudsen JS Baggesen LM Lajer M et al.Changes in SGLT2i and GLP-1RA real-world initiator profiles following cardiovascular outcome trials: a Danish nationwide population-based study.PLoS One. 2020; 15e0229621Crossref Scopus (23) Google Scholar This trend remained consistent through 2021 and might reflect both positive uptake and implementation of the pleiotropy of renal and cardiac data on SGLT2 inhibitors that has been emerging since 2015 and the reduced cost of SGLT2 inhibitors. In the study by Malik and colleagues,1Malik ME Butt JH Strange JE et al.Initiation of SGLT2 inhibitors and GLP-1 receptor agonists according to level of frailty in people with type 2 diabetes and cardiovascular disease in Denmark: a cross-sectional, nationwide study.Lancet Healthy Longev. 2023; (published online Sept 18.)https://doi.org/10.1016/S2666-7568(23)00164-2Google Scholar the probability of initiating therapy with either an SGLT2 inhibitor or a GLP-1 receptor agonist was significantly lower for people who were moderately frail or severely frail than for people who were non-frail, even after adjustment for age, sex, socioeconomic status, year of inclusion, duration of type 2 diabetes, duration of cardiovascular disease, polypharmacy, and comorbidity. Frailty was not associated with the probability of initiating a GLP-1 receptor agonist after adjustment for confounders, yet was a significant factor impeding prescription of an SGLT2 inhibitor. SGLT2 inhibitors affected the estimated glomerular filtration rate, volemic status, and predisposition to diabetic ketoacidosis of participants,5Pollack R Cahn A SGLT2 inhibitors and safety in older patients.Heart Fail Clin. 2022; 18: 635-643Summary Full Text Full Text PDF PubMed Google Scholar possibly leading to increased perceived risk of their use in people who are frail. However, analyses of the DAPA-HF6Butt JH Dewan P Merkely B et al.Efficacy and safety of dapagliflozin according to frailty in heart failure with reduced ejection fraction: a post hoc analysis of the DAPA-HF trial.Ann Intern Med. 2022; 175: 820-830Crossref PubMed Scopus (35) Google Scholar and DELIVER7Butt JH Jhund PS Belohlávek J et al.Efficacy and safety of dapagliflozin according to frailty in patients with heart failure: a prespecified analysis of the DELIVER trial.Circulation. 2022; 146: 1210-1224Crossref PubMed Scopus (2) Google Scholar trials showed consistency of efficacy and safety outcomes irrespective of frailty, alleviating some of these concerns. A larger proportion of people in these trials were defined as severely frail than in the observational study by Malik and colleagues, however, people who are severely frail display substantial heterogeneity, and clearly those participating in a clinical trial possess the minimal proficiencies required for participation (eg, the ability to ambulate to the clinical site and sufficient cognitive skills). Therefore, although these subanalyses are reassuring as they showed similar efficacy and safety of dapagliflozin irrespective of frailty status, these data cannot be extrapolated across the spectrum of people who are frail. The relatively low prescription rate of SGLT2 inhibitors and GLP-1 receptor agonists in people who are frail might be due to justifiable considerations. However, their alternatives should be considered. Aiming for reasonable postprandial glycaemic control in an older person might mandate a choice between a DPP-4 inhibitor, which is safe in this population but less efficacious than GLP-1 or insulin in its glucose-lowering effect;2ElSayed NA Aleppo G Aroda VR et al.Pharmacologic approaches to glycemic treatment: standards of care in diabetes—2023.Diabetes Care. 2023; 46: S140-S157Crossref PubMed Scopus (0) Google Scholar a GLP-1 receptor agonist; or short-acting insulin. In this context, short-acting insulin has the highest risk of hypoglycaemia, a major hazard in older people (appendix).8Billings LK Agner BFR Altuntas Y et al.The benefit of insulin degludec/liraglutide (IDegLira) compared with basal-bolus insulin therapy is consistent across participant subgroups with type 2 diabetes in the DUAL VII randomized trial.J Diabetes Sci Technol. 2021; 15: 636-645Crossref PubMed Scopus (3) Google Scholar Similarly, improved control of advanced heart failure can be achieved by prescribing an SGLT2 inhibitor instead of increasing the dose of furosemide; a renal protective effect with a reduction in cardiovascular death and admission to hospital for heart failure has been observed in SGLT2 inhibitors but not in furosemide.9Kim SJ Kim BJ Im SI Kim HS Heo JH Effects of empagliflozin on diuretics reduction in outpatient heart failure patients.Int J Heart Fail. 2022; 4: 183-192Crossref PubMed Google Scholar, 10van Poelgeest EP Handoko ML Muller M et al.Diuretics, SGLT2 inhibitors and falls in older heart failure patients: to prescribe or to deprescribe? A clinical review.Eur Geriatr Med. 2023; (published online Feb 3.)https://doi.org/10.1007/s41999-023-00752-7Crossref Scopus (5) Google Scholar Thus, although reasonable caution might be the reason for the observed prescription patterns, they might also be driven by clinical inertia. Although Malik and colleagues call for broader use of SGLT2 inhibitors and GLP-1 receptor agonists in older people who are frail due to their increased absolute benefit and to emerging data of these agents as agents to treat frailty and prevent its progression, more data regarding efficacy, safety, and cost-effectiveness are needed. For example, the effects of drug-induced weight loss on sarcopenia, bone mass, frailty, and falls in older people have yet to be studied.11DiMilia PR Mittman AC Batsis JA Benefit-to-risk balance of weight loss interventions in older adults with obesity.Curr Diab Rep. 2019; 19: 114Crossref PubMed Scopus (0) Google Scholar As the use of these agents in people who are frail is gradually increasing, the accumulation of more real-world efficacy and safety data is expected. Notwithstanding the limitations of real-world evidence, these data could provide useful information to further guide the correct use of SGLT2 inhibitors and GLP-1 receptor agonists for everyone, including people who are frail. The personalisation of care remains integral, particularly in people who are frail. Multiple subtle variables are not captured in large datasets, such as minimal cognitive impairment, presence of a supporting family or caregiver, and overall self-management capacity. These considerations are included in the global assessment of a person on a one-to-one basis and are important factors in the choice of medications. AC receives personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, and Pfizer. IH declares no competing interests. Editorial note: The Lancet Group takes a neutral position with respect to territorial claims in institutional affiliations. Download .pdf (.15 MB) Help with pdf files Supplementary appendix Initiation of SGLT2 inhibitors and GLP-1 receptor agonists according to level of frailty in people with type 2 diabetes and cardiovascular disease in Denmark: a cross-sectional, nationwide studyIn people with type 2 diabetes and cardiovascular disease in Denmark, frailty was associated with a significantly lower probability of SGLT2-inhibitor or GLP-1 receptor-agonist initiation, despite their benefits. Formulating clear and updated guidelines on the use of SGLT2 inhibitors and GLP-1 receptor agonists in people who are frail with type 2 diabetes and cardiovascular disease should be a priority. Full-Text PDF Open Access